1. Field of the Invention
This invention relates to compositions for use in the nutritional treatment of chronic renal failure (uremia). More specifically, this invention relates to mixtures of mixed salts formed between branched-chain alpha-keto acids and basic L-amino acids. The compositions can be used in conjunction with a 20-30 g/day mixed quality protein diet, and a vitamin and mineral supplement.
2. Summary of the Prior Art
Salts of basic L-amino acids, such as L-arginine and L-ornithine, and alpha-keto analogs of branched-chain essential amino acids, namely alpha-ketoisocaproate, alpha-ketoisovalerate and alpha-keto-beta-methylvalerate are disclosed in U.S. Pat. Nos. 4,228,099, 4,296,127 and 4,320,146, for use in the treatment of hepatic disorders characterized by hyperammonemia and portal systemic encephalopathy, and for treatment of renal failure.
Branched-chain keto acids, and alpha-ketoisocaproate in particular, are known to exhibit a nitrogen- or protein-sparing effect in patients with chronic renal failure. That is, branched-chain keto acids reduce urinary nitrogen loss. These keto acids have been used to improve the nitrogen balance in patients suffering from a number of different nitrogen wasting conditions.
Keto acid analogs are also known to be adequate nutritional substitutes for several of the essential amino acids. Substitution of keto analogs for essential amino acids makes possible a reduction in the nitrogen intake of uremic patients Reduction in dietary nitrogen intake may produce symptomatic benefit in patients whose blood urea nitrogen concentrations are high, simply by ameliorating the toxicity of urea itself. However, the nitrogen-sparing effect of keto analogs is clinically much more significant than the anticipated reduction in blood urea nitrogen.
Ideally, the most effective nutritional regimen for the treament of chronic renal failure in the pre-dialysis phase would be one that maintains protein nutrition as well as energy balance while minimizing the intake of those components of protein-containing foods which contribute to uremic toxicity. Protein-rich diets not only increase urea levels, but also increase accumulation of phosphates, sulfates and numerous organic acids and amines, substances that contribute to uremic toxicity. Protein restriction and concomitant phosphorus restriction appear to retard the rate of progression of chronic renal insufficiency.
A number of efforts have been made to optimize the nutritional treatment of chronic renal failure. For example, a 20 to 30 g/day protein diet supplemented with essential amino acid keto-analogs as calcium salts has been used. However, this approach suffers from the fact that the calcium salts of ketoanalogs are generally unpalatable and thus must be taken as coated granules or as tablets. Also the circulating concentrations of amino acids remain abnormal on this regimen, as they do on supplements based on essential amino acids themselves.
Recently, a new dietary regimen, in which the calcium salts of keto analogs have been replaced by mixed salts formed between branched-chain alpha-keto acids and basic L-amimo acids, has been used to treat chronic renal failure. These mixed salts have been found to be more soluble and less unpalatable than the calcium salts of the keto analogs and therefore may be taken as powder dissolved in water or fruit juice. E. Abras et al., "Mixed Salts of Basic Amino Acids with Branched-Chain Keto Acids," Metabolism and Clinical Implications of Branched Chain Amino and Ketoacids M. Walser and J. R. Williamson eds. Elsevier/North-Holland, New York (1981) 593; W. E. Mitch et al., "Long Term Effects of New Ketoacid - Amino Acid Supplement in Patients With Chronic Renal Failure," Kidney Int. 22 (1982) 48-53.
A treatment regimen incorporating one of these mixtures ("EE") has been found to yield a neutral nitrogen balance, and to raise the levels of tyrosine and threonine in plasma to normal. M. Walser et al., "Supplement Containing Amino Acids and Keto Acids," Kidney Int. 24 (1983) S285-S289. Data sufficient to assess the progression of renal failure for six months before and during treatment with this mixture was obtained for seven patients. The results show arrested progression, on the average, during administration of the mixture. W. E. Mitch et al., "The Effects of Protein Restriction Plus Keto Acids on Progression of Chronic Renal Failure" (Abst.) Clin. Res. 31 (1983) 437.
However, further improvement in "EE" mixture is desirable. The "EE" mixed salt supplement is prepared by mixing ten different constituents. The large number of constituents increases the difficulty of preparation of the supplement as well as the associated costs. In addition, since the shelf life of the mixture is limited by the storage stability of the least stable of the individual constituents of the mixture, mixtures with large numbers of constituents tend to have a shorter shelf life than those with a relatively small number of constituents. Thus, it is desirable to obtain a supplement having fewer constituents and which shows the same effectiveness in arresting the progression of chronic renal failure as dietary supplement "EE."